Transcriptional activation of the suppressor of cytokine signaling-3 (SOCS-3) gene via STAT3 is increased in F9 REX1 (ZFP-42) knockout teratocarcinoma stem cells relative to wild-type cells

JOURNAL OF MOLECULAR BIOLOGY

卷:377

Review

Xu, Juliana¹  Sylvester, Renia¹  Tighe, Ann P.¹  Chen, Siming¹  Gudas, Lorraine J.¹ 

[1] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10021 USA

关键词: retinoic acid;    dibutyryl cyclic AMP;    zinc finger transcription factor;    stem cells;    cancer;   

DOI  :  10.1016/j.jmb.2007.12.038

来源: Elsevier

【 摘 要 】

Rex1 (Zfp42), first identified as a gene that is transcriptionally repressed by retinoic acid (RA), encodes a zinc finger transcription factor expressed at high levels in F9 teratocarcinoma stem cells, embryonic stem cells, and other stem cells. Loss of both alleles of Rex1 by homologous recombination alters the RA-induced differentiation of F9 cells, a model of pluripotent embryonic stem cells. We identified Suppressor of Cytokine Signaling-3 (SOCS-3) as a gene that exhibits greatly increased transcriptional activation in RA, cAMP, and theophylline (RACT)-treated F9 Rex1(-/)-cells (similar to 25-fold) as compared to wild-type (WT) cells (similar to 2.5-fold). By promoter deletion, mutation, and transient transfection analyses, we have shown that this transcriptional increase is mediated by the STAT3 DNA-binding elements located between -99 to -60 in the SOCS-3 promoter. Overexpression of STAT3 dominantnegative mutants greatly diminishes this SOCS-3 transcriptional increase in F9 Rex1(-/)-cells. This increase in SOCS-3 transcription is associated with a four-to fivefold higher level of tyrosine-phosphorylated STAT3 in the RACT-treated F9 Rex1(-/)-cells as compared to WT. Dominant-negative Src tyrosine kinase, Jak2, and protein kinase A partially reduce the transcriptional activation of the SOCS 3 gene in RACT-treated F9 Rex1 null cells. In contrast, parathyroid hormone peptide enhances the effect of RA in F9 Rex1(-/-) cells, but not in F9 WT. Thus, Rex1, which is highly expressed in stem cells, inhibits signaling via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, thereby modulating the differentiation of F9 cells. (c) 2007 Elsevier Ltd. All rights reserved.

【 授权许可】

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